Our long-term objective is to understand how neuromodulation and synaptic integration shape information[unreadable] processing in the olfactory system. This objective is addressed in the main olfactory bulb (MOB), the first[unreadable] central relay station for olfactory information. The endocannabinoid system is an important neuromodulatory[unreadable] system, which involves cannabinoid receptors, CB1R, and their endogenous activators, endocannabinoids[unreadable] (eCBs). In the MOB, neurons express high levels of CB1R, but its cellular and network functions are[unreadable] unknown. Our new preliminary data shows that CB1R agonists and antagonists alter the membrane potential[unreadable] and response to synaptic input of GABAergic interneurons, granule cells, and the membrane potential and[unreadable] firing pattern of principal neurons, mitral cells. Based on our preliminary data, the hypothesis is that eCBs[unreadable] prominently modulate membrane properties of MOB neurons, change the response to synaptic input, and[unreadable] regulate the neural network of the MOB. Consequently, the overall aim of this proposal is to determine the[unreadable] role of eCBs and CB1R for neural signaling in the MOB. In Specific Aim 1, the hypothesis will be tested that[unreadable] CB1R directly regulates the excitability of mitral cells and granule cells in a slice preparation of the mouse[unreadable] MOB. Do eCBs mediate self-inhibition of mitral cells and granule cells, i.e., are eCBs released by a neuron[unreadable] and target CBIRs on the same neuron? In Specific Aim 2, the hypothesis will be tested that CB1R regulates[unreadable] synaptic responsiveness of mitral cells and granule cells. Do eCBs serve as retrograde signaling molecules[unreadable] in the MOB between post- and presynaptic neurons to regulate presynaptic transmitter release? The[unreadable] interaction of the eCB system with another modulatory system, the metabotropic glutamate receptor (mGluR)[unreadable] system will be investigated to test the hypothesis that both systems are functionally interrelated. The[unreadable] experimental approach includes whole-cell patch-clamp recording and intracellular labeling of MOB neurons[unreadable] visualized with near infrared differential interference optics, use of mGluR knockout (KO) mice and CB1R KO[unreadable] mice, and characterization of cellular, membrane, pharmacologic and network properties of eCB-modulated[unreadable] neural processing in the MOB. Our findings help to explain the properties of marijuana at the cellular level[unreadable] through eCB-mediated synaptic processing in the MOB and eventually lead to a better understanding of drug[unreadable] addiction and could pave the way for new treatment strategies to prevent the use of drugs.[unreadable]